Molecular function of vitamins and hormones, metabolism of vitamins A and D
Professor H. F. DeLuca's laboratory has been devoted to the understanding of metabolism and mechanism of action of vitamins A and D. Initially, work in this group centered around describing which forms of vitamin D and vitamin A are active in correcting deficiency disease. In particular, in the 1960's by means of isolation, chemical identification and chemical synthesis, this laboratory demonstrated that vitamin D itself is biologically inactive and must be modified by sequential action by the liver and kidney to prepare the hormone derived from vitamin D, namely 1,25-dihydroxyvitamin D3. Not only the hormonal form but many of its analogs were chemically synthesized in this research group and developed for the treatment of a variety of diseases including osteoporosis, vitamin D dependency rickets, and bone disease of kidney failure. More recently, this laboratory has devoted its efforts to understanding how 1,25-dihydroxyvitamin D3 functions in the target tissues. A receptor which recognizes this hormone has been identified in target tissue nuclei. It has been cloned and its entire amino acid and nucleotide coding sequence has been determined. We have successfully expressed it in large quantities in baculovirus and bacteria and are in the process of crystallizing the protein for three-dimensional structural work. Response elements or specific DNA sequences to which the receptor binds in order to initiate transcription of the genes have also been identified. Other molecular biology techniques are being applied to isolate genes and identify the proteins that are made in response to 1,25-dihydroxyvitamin D3. By locating the receptor in tissues not previously recognized as targets of vitamin D action, new functions for vitamin D have been identified. It is now clear that 1,25-(OH)2D3 serves as a developmental hormone as well as a hormone responsible for regulating calcium and phosphorus. It has also been found to be necessary for reproductive function in females, for the immune system, and for the development of giant osteoclasts responsible for remodeling bone. Our laboratory uses a combination of molecular biology techniques, organic chemical techniques, physiological techniques, and cell biology techniques to learn the molecular mechanism of action of these fat-soluble substances. There is considerable effort dedicated to collaboration with the medical world for the application of the newly synthesized analogs of the vitamin D compounds and of vitamin A compounds for the treatment of disease. The most recent application has been to prevent and arrest such autoimmune diseases as multiple sclerosis and rheumatoid arthritis, and as an anti-transplant rejection drug.